Oxidative-nitrosative stress and poly(ADP-ribose) polymerase in cardiovascular pathophysiology, ischemia/reperfusion injury and diabetic complications: cellular and molecular mechanisms. Oxidative/nitrosative stress-PARP pathway is a key event in the development of cardiovascular and other organ dysfunction in various diseases, and also in the development of ischemic-reperfusion damage. Novel drug candidates targeting this pathway entering or being evaluated in trials for cancer and a variety of critical care diseases associated with reperfusion injury and inflammation, including but not limited to ischemic stroke, acute respiratory distress syndrome, thoraco-abdominal aortic aneurism (TAAA), repair surgery and the prevention of complications associated with cardiopulmonary bypass surgery, myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). In collaboration with Dr. Liaudet we have recently demonstrated that the influence of oxidants on NF-kappaB, a master regulator of inflammation, is entirely context-dependent, and that the final outcome (activation versus inhibition) depends on a balanced inhibition of protein phosphatase 2A and IKK by oxidant species. These findings provide a new conceptual framework to understand the role of oxidant stress during inflammatory processes. Cardiovascular complications are the most common cause of morbidity and mortality in diabetic patients. The presence of myocardial dysfunction independent of coronary artery disease in diabetes, known as "diabetic cardiomyopathy," has been well documented in both humans and animals. We have recently demonstrated that diabetic cardiomyopathy or exposure of primary human cardiomyocytes to prolong concentrations of high glucose is associated with the activation of NF-kappaB and consequent upregulation of various inflammatory, pro-oxidant and cell death pathways coupled with attenuation of pro-survival signaling. Our impeding studies will be directed towards the identification of novel therapeutic targets to counteract these pathological processes. We are particularly interested in the development of novel mitochondrial targeted antioxidants and identification of plant-derived natural compounds with potent antioxidant and anti-inflammatory effects (in collaboration with Drs. Kalyanaraman, Wink, Mechoulam and Pertwee). There is accumulating evidence indicating that endocannabinoids and synthetic cannabinergic ligands exert potent antioxidant, cytoprotective and immunomodulatory effects. Our previous studies showed that the non-psychoactive cannabinoid cannabidiol attenuated the high glucose-induced endothelial cell activation and barrier disruption, which are crucial early event underlying the development of various diabetic complications and atherosclerosis. Our recent studies have also been examining the role of endocannabinoid system in the development of diabetic cardiovascular complications using mouse models of type 1 diabetes, as well as the antioxidant/anti-inflammatory effects of various natural and synthetic cannabinergic ligands (in collaboration with Prof. Raphael Mechoulam) on the development of oxidative stress and inflammation, and on cardiac and vascular dysfunction associated with advanced aging and doxorubicin-induced heart failure, ischemia-reperfusion, conditions also known to be associated with increased oxidative/nitrosative stress and PARP activation, in relevant animal models. Our present and future collaborative studies with Dr. Hasko will also evaluate the role of adenosine receptors in regulation of the inflammation and explore a possibility of an interplay of these 2 endogenous systems (adenosine and endocannabinoid). Role of endocannabinoid system in tissue injury and inflammation. Our previous studies have demonstrated that oxidative/nitrosative stress is involved in the activation of the endocannabinoid system (ES), and the stimulation of peripheral CB2 cannabinoid receptors protected against I/R-induced tissue injury by decreasing endothelial cell activation and inflammatory response and interrelated oxidative/nitrosative stress. In recent studies we have found that CB1 receptor activation in primary human endothelial cells and cardiomyocytes, or in relevant animal models of heart failure leads to activation of p38 and JNK MAPKs, ROS generation and cell death. We also found opposing roles of CB1 and CB2 receptors in regulating oxidative/nitrosative stress and inflammation associated with a clinically relevant nephropathy model. Our impending studies will also be directed towards the understanding of the mechanisms of the activation of the endocannabinoid system during reperfusion injury and on the further elucidation of the role of endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes in collaboration with Dr. Cravatt) in various models of cardiomyopathy and heart failure (e.g. doxorubicin-induced heart failure). Our future collaborative studies with Drs. George Kunos, Bin Gao and Byoung-Joon Song will also be directed towards the investigation of the role of oxidative/nitrosative stress and endocannabinoid system in various other models of liver and metabolic disorders. The above mentioned studies may identify new pharmacological targets in various forms of tissue injury and cardiovascular dysfunction associated with increased inflammation and oxidative stress. Role of oxidative-nitrosative stress and apoptosis in ethanol-induced tissue-damage. Moderate and heavy drinking may significantly influence cardiovascular function and aging in different ways. During the course of the last decade, several research groups have reported that, in animal models of myocardial ischemia/reperfusion ethanol and non-ethanolic components of wine may have a specific protective effect on the myocardium, independent of the classical risk factors implicated in vascular atherosclerosis and thrombosis. Apoptosis is a mechanism of cell death implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in the cardiac muscle and liver, and there is also evidence of skeletal muscle apoptosis in long-term high-dose alcohol consumers. Apoptosis is present to a similar degree in the heart muscle of high-dose alcohol consumers and long-standing hypertensive subjects and is related to structural damage. In a collaborative study with Dr. Gao we have found dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice. Our recent/impending studies will be focused on the understanding of the mechanisms of ethanol-induced oxidative/nitrosative stress, inflammation and cell death in the cardiovascular system and also in the liver. We will use clinically relevant models of aging (Fisher rats developed by National Aging Institute) to address the effects of ethanol on the course of oxidative/nitrosative stress and inflammation associated with aging.